Cancers are complex systems commonly associated with a robust fibroinflammatory stromal response, or desmoplastic reaction. This is highly relevant as it is now recognized that, in many solid tumors, the stromal compartment and its local microenvironments significantly influence disease progression. Through disease progression this desmoplastic reaction continues and often intensifies, offering critical support to malignant cells as they progress to invasive and often fully metastastic disease while also providing drug-free sanctuaries that limit access of small molecule therapies. Likewise, even the earliest stages of disease are associated with a robust immune reaction that evolves with disease progression. Here tumor microenvironments appear to form sanctuaries for immune evasion and in fact are comprised, in part, of infiltrated immune cells that have been subverted to act as active collaborators that enable tumor progression. Interestingly, while robust biochemical stimuli are present in tumors, they are not the only factor. These microenvironments also provide robust physical cues that conspire to promote disease progression. For instance, in solid tumors there are fundamental roles of extracellular matrix stiffness, composition and architecture that profoundly influence outcome. However, to date, the molecular and physical mechanisms by which matrix stiffness and architecture, and their relative contributions, influence tumor cell behavior are not well known. Here, we propose specific and integrated experiments and modeling to explicitly investigate the physical and molecular mechanisms by which the tumor microenvironment regulates disease progression as a function of the underlying carcinoma genetics. Quantitative analysis and parameterization of data will facilitate model development and model predictions will be tested experimentally. Specifically, we will employ a series of 2D and 3D assays with varying stiffness and architecture of increasing complexity, and multiscale network modeling, to parse out the relative contributions of contact guidance cues and durotactic effects in complex microenvironments. Integration of chemical gradients will be used to parse out dominance, antagonism or synergy between chemical and physical cues. Further, we hypothesize that physical cues in the cellular microenvironment drive communication between different tumor cell populations and regulate immune cell infiltration and function. Thus, we seek to identify regimes where manipulating operant physical characteristics of a tumor reduces carcinoma cell advancement while simultaneously hampering immune evasion and promoting the antitumor response.